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A Thiol-Mediated Three-Step Ring Expansion Cascade for the Conversion of Indoles Into Functionalized Quinolines

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A Thiol-Mediated Three-Step Ring Expansion Cascade for the Conversion of Indoles Into Functionalized Quinolines This is a repository copy of A Thiol-Mediated Three-Step Ring Expansion Cascade for the Conversion of Indoles into Functionalized Quinolines. White Rose Research Online URL for this paper: https://eprints.whiterose.ac.uk/171748/ Version: Accepted Version Article: Inprung, Nantachai, James, Michael J orcid.org/0000-0003-2591-0046, Taylor, Richard J K orcid.org/0000-0002-5880-2490 et al. (1 more author) (2021) A Thiol-Mediated Three-Step Ring Expansion Cascade for the Conversion of Indoles into Functionalized Quinolines. Organic letters. ISSN 1523-7052 https://doi.org/10.1021/acs.orglett.1c00205 Reuse This article is distributed under the terms of the Creative Commons Attribution-NonCommercial (CC BY-NC) licence. This licence allows you to remix, tweak, and build upon this work non-commercially, and any new works must also acknowledge the authors and be non-commercial. You don’t have to license any derivative works on the same terms. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ A thiol-mediated three-step ring expansion cascade for the conver- sion of indoles into functionalised quinolines Nantachai Inprung, Michael J. James*, Richard J. K. Taylor*, William P. Unsworth* Department of Chemistry, University of York, Heslington, York, U.K., YO10 5DD ABSTRACT: An operationally simple, high yielding three-step cascade process is described for the direct conversion of indole- tethered ynones into functionalised quinolines. - -step dearoma- tising spirocyclisation, nucleophilic substitution and one-atom ring expansion reaction cascade under remarkably mild con- ditions. In addition, a novel route to thio-oxindolesA single is described, ‘multi tasking’ which thiol was reagentdiscovered is used by serendipity. to promote a three Cascade reactions (chemical processes by which two or Scheme 1. Transformations of indole-tethered ynones. more consecutive reactions take place in a single pot-pro- cess, also wide utility in synthetic chemistry.1,2 Incorporating cascade reaction sequencesknown as into‘tandem’ synthetic or ‘domino’ routes canreactions) significantly have improve the speed and ease with which complex target mol- ecules can be prepared, and often means that the direct han- dling of reactive, unstable and/or toxic species can be avoided by forming these intermediates in situ. This manuscript concerns a three-step cascade reaction sequence, starting from indole-tethered ynones 1 (Scheme 1). In recent years, ynones of this type have emerged as val- uable precursors for the preparation of a diverse array of molecular scaffolds.3-6 For example, our groups and others have shown that the activation of the alkyne moiety of 1 promotes efficient dearomatising spirocyclisation7,8 to form medicinally important spirocyclic indolenines 2;9,10 this is most commonly done using π-acidic catalysts (especially Ag(I) species), although Brønsted acids, palladium(II) com- plexes and electrophilic halogenation reagents can also be used (1 → 2, Scheme 1a, Step 1).3,11,12 Our groups have also shown that dearomatisation works well on 2-halogenated indoles (i.e. 1 where X = Cl, Br or I) and that the resulting We started by exploring reactivity of model 2-bromo indoleninyl halide products (i.e. 2 where X = Cl, Br or I) can ynone 1aBr with various reagents (NuH) that we thought be transformed further via reaction with nucleophiles, or might have the required acidity and nucleophilicity to pro- via Pd-catalysed cross-coupling, to substitute the halide for mote its conversion into a quinoline of the form 4. Phenol 15 various other groups (2 → 3, Scheme 1a, Step 2).5 Finally, was tested first, and added to a solution of 1aBr in DCE, but our groups and others have demonstrated that spirocyclic no reaction was observed after stirring at RT or 60 °C (en- indolenines of the form 3 will rearrange via a one-atom ring tries 1 and 2, Table 1). Next, TFA was included as an additive expansion reaction13 to form annulated quinolines, with in the reaction, which led to the consumption of the starting both acidic and basic reagents able to promote this trans- material, but the only tractable products observed were ox- indole 7a (presumably formed via acid-mediated dearoma- formation (3 → 4, Scheme 1a, Step 3).6 tising spirocyclisation and hydrolysis of the resulting spiro- Efficient protocols for each of the individual steps repre- cycle 5a),5 and bromoquinoline 8, which likely formed via a sented in Scheme 1a are therefore established, but three- Bronsted acid-mediated rearrangement of 5a (c.f. step 3).6b steps are still required to generate functionalised quino- A more acidic NuH reagent, 4-nitrophenol, was tested but lines 4 from ynones 1. Quinolines are found in many mar- no reaction was observed at RT (entry 4), while at 60 °C the 14 keted drugs, as well as in various other applications. Based same side products 7a and 8 were formed (entry 5). We on a growing understanding of each of the three individual then decided to move on to species of similarly acidity to 3,5,6 processes discussed above, we recognised that certain phenol, but also more nucleophilic, and pleasingly, thiols16 reagents may be able to promote all three steps and enable were found to possess this attractive combination of prop- the transformation of 1 into 4 via a single-cascade process erties; using n-propyl thiol, no conversion was observed at (Scheme 1b); such a reagent would need to act as an acid to RT (entry 6), but excellent conversion into the desired quin- ø promote step 1, a nucleophile in step 2, and a Br nsted acid oline 4a was observed upon heating to 60 °C (entry 7). Fur- to promote step 3. The successful realisation of this strategy thermore, the more acidic thiophenol was able to promote is reported herein, with thiols emerging as the optimum the conversion of 1aBr into quinoline 4b smoothly at RT (en- - reagent class capable of promoting the en- try 8). visaged cascade, under remarkably mild and operationally simple‘multi tasking’ conditions. Table 1. Initial optimisation[a] was 4-NMe2-substituted ynone 1fBr; in this case, spirocyclic indoleninyl bromide 5b was isolated in 89% yield.19 Despite not delivering the expected quinoline, the isolation of spiro- cycle 5b does provide indirect mechanistic evidence for the intermediacy of indoleninyl halides in the reaction cascade (see later for discussion). Finally, by replacing the thiol with benzeneselenol, the analogous selenide product 4bSe was obtained in 62% yield. The unexpected isolation of thio-oxindole 9a during the synthesis of 4n prompted additional studies, in part to bet- ter understand this side reaction, but also to try and harness it productively, as a new way to make thio-oxindoles.20 Our theory for how thio-oxindole 9a formed is summarised in en- Nucleophile (NuH) Temp Outcome[b] Scheme 3a. The reaction is likely to have started as ex- try pected, and thus proceeded through the normal dearoma- 1 Phenol (Nu = PhO) RT No reaction tising spirocyclisation and nucleophilic substitution steps (i.e. steps 1 and 2). This would generate spirocycle 10, and 2 Phenol (Nu = PhO) 60 °C No reaction at this point, it appears that the route diverges, with some Phenol (Nu = PhO) with 7a (62%) 3 RT of the material going on to form quinoline 4n in the usual 1 equiv. TFA 8 (21%) way, and the rest undergoing debenzylation, either via an 4-Nitrophenol SN1-type pathway as drawn, or the analogous SN2-type 4 RT No reaction cleavage (not shown). To test this idea and improve the (Nu = 4-NO2C6H4O) yield of thio-oxindole 9a, the reaction was repeated using 4-Nitrophenol 7a (35%) the silylated thiol Ph3SiSH 11; the idea was that the weak 5 60 °C (Nu = 4-NO2C6H4O) 8 (45%) Si S would cleave more easily than the S Bn bond in 10, and n-Propyl thiol facilitate thio-oxindole formation via a desilylative mecha- 6 RT No reaction nism.– This idea worked well; the reaction– of ynone 1aBr with (Nu = n-PrS) Ph3SiSH 11 using the standard 60 °C procedure led to the n-Propyl thiol formation of thio-oxindole 9a in 82% isolated yield 7 60 °C 4a (95%) (Nu = n-PrS) (Scheme 3b). The same procedure was applied to other 2- Thiophenol halo-indole-tethered ynones, with thio-oxindoles 9b 9d 8 RT 4b (93%) (47 85%) prepared in the same way. (Nu = PhS) A proposed mechanism for the three-step cascade is out– - [a] 1aBr (1 equiv) and NuH (1.6 equiv) were stirred in DCE lined– in Scheme 4a. The cascade likely initiates with (0.1 M, degassed) for 20 h at the specified temperature. [b] dearomatising spirocyclisation, promoted by the relatively Yields are isolated material after column chromatography. acidic thiol (A B, step 1, Scheme 4a); protic acids have With conditions for the cascade established, attention been shown to promote spirocyclisation of related turned to examining the reaction scope. A range of aromatic ynones,3b,6b and→ the isolation of spirocyclic indoleninyl bro- thiols were tested (Scheme 2A), and all reacted well with mide 5b discussed earlier lends further support to this no- ynone 1aBrv; quinolines 4b k were all prepared in this man- tion. The resulting iminium-thiolate ion pair 2 may then un- ner, generally in high yield, under the standard RT condi- dergo facile nucleophilic substitution to afford substituted tions using a range of electronically– diverse substituted thi- spirocycle 12 (step 2).5 The rearrangement of 12 into 17 is ophenols.
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